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One swallow does not make a summer, and one positive clinical trial does not make an Alzheimer’s drug. In 2007, expectations for Dimebon, an old antihistamine, soared on results of a positive Phase 2 trial in AD patients in Russia. Dimebon appeared not only to slow cognitive decline, but even to improve cognition. The Alzheimer’s community eagerly awaited another positive sighting; alas, it now appears Dimebon is facing a winter of discontent. Yesterday, the drug’s sponsors released highly anticipated data from the Phase 3 CONNECTION study. Dimebon failed to have any significant effect in two co-primary and several secondary outcome measures. The news comes as a bitter disappointment to patients and families desperately seeking a treatment for this progressive, incurable disease.

Within hours of the widely reported news, the stock price of Medivation Inc., Dimebon’s sponsor, tumbled 67 percent (see related stories in the The Wall Street Journal, the The Financial Times, and The New York Times). Whether this turn of events spells the beginning of the end of yet another hoped-for AD drug remains to be seen. “That one study has failed does not necessarily mean it’s the drug; it could have been the trial design, or something else. But the odds of success have certainly gone down,” said Murali Doraiswamy, Duke University Medical Center, Durham, North Carolina. Doraiswamy was not involved in this study but is an investigator for CONCERT, a 12-month trial of Dimebon in mild-moderate AD patients who are also taking the cholinesterase inhibitor donepezil.

The CONNECTION was co-sponsored by Pfizer Inc., whose key patent on donepezil (trade name Aricept) is set to expire this November. Pfizer made a deal with Medivation worth $725 million for worldwide rights to Dimebon and pays 60 percent of the drug’s development costs.

The randomized, double-blind, placebo-controlled CONNECTION trial recruited 598 patients who were not taking other anti-dementia drugs. Patients enrolled at 63 sites in North America, Europe, and South America. They were split into three groups, two receiving 5 or 20 mg Dimebon three times a day, respectively, the third a placebo. The co-primary endpoints were cognition as measured by the ADAS-cog (the Alzheimer’s Disease Assessment Scale-cognitive subscale) and global function as measured by the CIBIC+ (Clinician’s Interview-Based Impression of Change-Plus Caregiver Input). According to information Medivation released yesterday on its website and in a teleconference, after six months of treatment there was no significant difference between either drug group and the controls. The secondary endpoints fared no better. On the Mini-Mental State Examination (MMSE), another measure of cognition, the placebo group actually outperformed the drug groups, though the difference was not statistically significant. On the Neuropsychiatric Inventory (NPI), the Dimebon group showed a slight improvement over placebo, but again the result was not significant. In terms of function, neither the placebo nor the Dimebon groups showed any significant change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative Study-Activities of Daily Living).

“Basically, the study did not meet its aim,” said Rachelle Doody, Baylor College of Medicine, Houston, Texas. Doody is a member of the Medivation medical scientific and advisory board who is involved in the analysis and reporting of the data. She holds stock options in Medivation and was the primary investigator of the earlier Phase 2 trial that appeared so successful (see ARF related news story and Doody et al., 2008). Speaking to why the prior trial and this one had such different outcomes, Doody told ARF, “You can never expect to get exact same numeric results in trials. I really don’t know at this point what might account for some of the differences. One thing we always think about is variability. Here we’ve introduced many countries, many languages, and changes of procedures in order to standardize approaches. We always worry about any impact of those features on what we see in drug-placebo differences.”

Some researchers were quick to point out that the study was not a complete failure, noting that neither the placebo group nor patients taking Dimebon worsened. “I’ve seen some of the press reports so far and I find them a little bit harsh and a little bit premature,” said Mark Smith, Case Western Reserve University, Cleveland, Ohio. Smith consults for Medivation. He also carries out preclinical analysis of Dimebon to understand how the drug might work, a question that is still unanswered (see ARF related news story). “I find the data un-interpretable and the whole trial un-interpretable because the placebo group did not decline. Therefore, you can’t really say that the drug failed,” Smith told ARF. “I would throw away the data, perhaps, but I would not throw away the drug. That would be throwing the baby out with the bathwater,” he said.

Other researchers found it harder to see a silver lining. “At the end of the day, all of the outcome measures were non-significant. The one cognitive measure that seemed to reach some degree of significance, or at least came close to it, actually favored placebo over the drug, so there does not seem to be any signal whatsoever in this study,” said Doraiswamy.

Lon Schneider, University of Southern California, Los Angeles, also doubted that the non-declining placebo group was the issue. “In the Phase 2 study, much of the effect was in an absolute improvement in the ADAS-cog by 1.9 points—and much was made by the authors that all outcomes improved substantially over baseline and that the effects were not driven by the worsening placebo group. But what you have in this study is essentially no improvement whatsoever,” he told ARF. “So even if the placebo group did not decline, there is still no separation.” Schneider also found it disconcerting that the MMSE data favored the placebo. Schneider has consulted for Medivation in the past, currently consults for Pfizer, and is an investigator in a Pfizer-sponsored trial.

These negative data come against a backdrop of lingering questions surrounding Dimebon’s rise to fame. The drug was originally developed in the 1980s as an antihistamine in Russia, where the pivotal Phase 2 AD trial was conducted. In 2001, Dimebon was patented as an NMDA receptor antagonist, but after the Phase 2 study, Medivation claimed the drug protected mitochondria, though it is not clear exactly how. Other researchers, including Ilya Bezprozvanny, University of Texas Southwestern Medical Center, Dallas, claim that this mitochondrial activity is too weak to be the mechanism of action in AD (see ARF related news story and Wu et al., 2008). Schneider agrees that while Dimebon may well bind the mitochondria permeability pore, which is one explanation for its mitochondrial effects, that is unlikely to be its mechanism of action in AD. “When you look at the molecule, it is heterocyclic with different conformations with multiple effects,” he told ARF. “It has effects on subtypes of several neurotransmitter receptors, including α adrenergic receptors, dopaminergic receptors, serotonin receptors, and also histamine receptor subtypes. The strongest effect is as an H1 antihistamine and serotonin 5-HT6 antagonist. So in a way it is pro-cholinergic and symptomatic, and it might work for Alzheimer’s if you had higher doses,” he said (see also Okun et al., 2010). He thinks it may possibly show efficacy for treating behavior, which is in keeping with the NPI favoring the Dimebon group in this CONNECTION study. “The NPI slight signal is the glimmer of hope, and might be detected in the moderate to severe AD studies because these patients have more behavior symptoms,” he said.

One biotechnology analyst, Eric Sharps of FourSquare Partners, questions if the compound used in U.S. trials is even the same as that used in the Phase 2 trial in Russia. In a wide-ranging critique of Dimebon, Sharps noted that in the Russian trial, the major side effect was dry mouth, which is consistent with the drug being an antihistamine, whereas in a recent U.S. trial of Dimebon for Huntington disease (see ARF related news story), the major side effect was headache. While that could reflect a different response by different populations, a simpler explanation might be that compounds synthesized in Russia and the U.S are not identical, Sharps contends. His 2009 analysis raised questions about Medivation and suggested that “there is little or no chance that Dimebon will demonstrate efficacy in Alzheimer's or Huntington's.” Sharps’s full report is publicly available for download.

Where do the companies go from here? Medivation has three other clinical trials ongoing for AD and one for HD (see ClinicalTrials.gov). Calls to both Medivation and Pfizer representatives were not returned but passed on to a public relations company who fielded questions on behalf of both sponsors. Its representative told ARF that AD and HD trials are still going forward with enrollment and that the companies are planning to submit further analysis of this trial’s data at an as-yet unspecified upcoming medical meeting. Meanwhile, scientists agreed that this setback may slow down enrollment for the remaining ongoing trials and that the chance of Dimebon obtaining FDA approval in the next year or so have dropped sharply.—Tom Fagan.